We have studied 32 unrelated families with a site-specific reciprocal translocation between chromosomes 11 and 22 [t(11;22) (q23;q11)]. In translocation heterozygotes 3:1 meiotic segregation occurs and results in abnormal progeny who carry the der(22) as a supernumerary chromosome. Phenotypic findings consistent with 47,XX (or XY), +der(22), t(11;22) include mental retardation, preauricular skin tag and/or sinus, ear anomaly, palate anomaly, micrognathia, congenital heart disease, and genital anomalies in males. The frequency of abortions among offspring of male and female heterozygotes is increased. Segregation analysis shows that the risk of unbalanced offspring to be born to female heterozygotes may be as high as 10%, and that there may be a significant risk to male heterozygotes as well. The overall carrier frequency among progeny of 11;22 translocation carriers is 70.6%. The occurrence of multiple 11;22 translocation events is supported by de novo occurrence of translocation, familial heteromorphic variants of the der(22), and varied racial and ethnic backgrounds of the families. To our knowledge, with the exclusion of centric fusion translocations, this represents the only example of nonrandom exchange in a constitutional chromosomal rearrangement.

Site‐specific reciprocal translocation, t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction

The field of human cytogenetics has changed considerably since 1891 when Hansemann studied chromosomes in human cells and attempted to assign a chromosome number to them. 1 The first important discovery was made in 1949 by Barr and Bertram when they observed the sex chromatin body, a small, darkly staining chromatin mass present in the interphase nuclei of females 2 (Fig 1, left). This discovery later made possible the presumptive diagnosis of Turner and Klinefelter syndromes by the simple analysis of a buccal smear. After 1956, when Tjio and Levan together developed a simple technique that made possible the study of human chromosomes, 3 the field progressed rapidly. During the ensuing five years, the causes of trisomy 13, 18, and 21 syndromes; Turner syndrome, and Klinefelter syndrome were established. The next five years saw the application of autoradiography for better identification of chromosomes and the delineation of more subtle chromosome

New chromosomal syndromes.

Non-disjunction plays a major role in generating aneuploidy in man. About 50% of spontaneous abortions are chromosomally abnormal and among these, trisomies constitute the major group (∼50%), followed by monosomy X (18%), triploidy (17%), tetraploidy (6%) and others. Over 30% of all trisomies are due to trisomy for chromosome 16. There seems to be an association between maternal radiation history and spontaneous abortions in the sence that the work reported, mothers of chromosomally abnormal foetuses have received higher mean gonadal doses relative to comparable controls. About 6% of babies who die perinatally are chromosomally abnormal and the majority are trisomics especially for group E chromosomes. The results of six major surveys of consecutive newborns show that 6 out of 1000 (0.6%) carry one or another kind of chromosome anomally. The breakdown is as follows: 0.22%, sex-chromosomal abnormalities; 0.14%, autosomal trisomies (+D, +E and +G); 0.19%, balanced structural rearrangements and 0.06%, unbalanced structural rearrangements and others. The frequency of “clinically significant” anomalies has been estimated to be about one-half of the total of all chromosomal abnormalities detected in newborns. The spontaneous “mutation rate” for numerical anomalies of chromosomes which result in liveborn children is about 15 × 10 −4 per gamete per generation (9.3 × 10 −4 for sex-chromosomal aneuploidies and 5.7 × 10 −4 for autosomal trisomies). Autosomal aneuploidies are associated with more severe phenotypic effects than sex-chromosomal aneuploidies. The majority of the sex-chromosomal aneuploidies are constituted by XXY, XYY, XXX and XO genotypes (and mosaics). Of these, while the XYY genotype can arise only through second division paternal non-disjunction, the others can arise as a result of either first or second division non-disjunction in either the father or the mother. There is evidence showing that in about 80% of XO (Turner's syndrome) individuals, the single remaining X is of maternal origin suggesting loss of the paternal-X. The frequency of sex-chromosomal aneuploidies in children born to survivors of the Hiroshima and Nagasaki bombings is higher than in controls, but the difference is not significant. Down's syndrome, which is one of the relatively better known autosomal aneuploidies in man, is due to trisomy for chromosome 21, translocation of chromosome 21 with another autosome (usually chromosome 14) or mosaicism for an extra chromosome 21. Trisomy 21 which accounts for 95% of the cases, is due to non-disjunction during gametogenesis in one of the parents, more often in the mother. With quinacrine fluorescent techniques, evidence has been obtained which shows that non-disjunction can occur either in the father or in the mother at first or second meiotic division. The incidence of primary trisomies for chromosome 21 shows a strong correlation with increasing maternal age and this is very extensively documented (gradual increase in risk from maternal age about 20 to 30–31 and a steeper increase thereafter). The data on the association between an increase in paternal age and Down's syndrome are conflicting although some data suggest that the risk may be high for fathers above 55 years of age. Satellite associations between acrocentric chromosomes have been observed in metaphase preparations of chromosomes of lymphocytes, but the questions of whether there are preferential associations between certain chromosomes, and if so, what their relevance is for trisomy, are not yet settled. Consequently it may be premature to extrapolate the findings in somatic cells to germ cells and to the possible origin of trisomies, including that of trisomy 21. The results of 9 retrospective and 3 prospective studies designed to examine whether parental irradiation may increase the risk of producing Down's syndrome have been published. The available evidence does suggest that there is no correlation between paternal radiation and Down's syndrome in the progeny, but is conflicting on the question of correlation between maternal irradiation and Down's syndrome. Thus, after nearly two decades of work on this aspect, no unequivocal answers are available. Both trisomy 18 (Edward's syndrome) and trisomy 13 (Patau's syndrome) are associated with severe phenotypic effects; the incidence rates are about one on 10 000 and one in 15 000 births, respectively. These trisomies are not compatible with survival to adulthood. Other, relatively rare trisomies include those for chromosomes 8 and 22. In Fig. 1 is presented a broad summary of the frequencies of different chromosomal anomalies and thier effects, relating these to one million conceptions (under the assumption that 15% of all conceptions are spontaneously aborted and 2% of the children die perinatally and making use of the different frequencies cited in the text with respect to the kinds of anomalies). The technique of fusion of human spermatozoa with golden hamster eggs, the details of which were published recently, appears to be a promising one since, this permits a direct analysis of the chromosome constitution of human spermatozoa and hopefully, studies on the effects of physical and chemical agents at a level that has hitherto been impossible.

The role of non-disjunction in aneuploidy in man. An overview.

A syndrome due to 3:1 meiotic segregation of balanced 11/22 translocation is defined from nine personally observed patients and 22 cases from the literature with apparently the same aberration. Frequent findings include a characteristic face with deepset eyes, flat nose, prominent upper lip, receding mandible and preauricular pits or tags, male genital hypoplasia, anal atresia or other anomalies of the anus, cleft palate, and congenital heart defect. Less frequent are severe reduction of the auricles, an additional pair of ribs, and hypoplasia of the diaphragm. Perinatal mortality is high. Growth is usually and psychomotor development is invariably and severely delayed. Balanced 11/22 translocations are apparently disproportionally frequent; as the balanced rearrangement is not easy to detect, it is important to be aware of it at the family investigation of cases with extra chromosomes similar to a No.22 or 22q-.The unbalanced products are most probably trisomic for both a segment of 22 (22q-) and a distal segment of 11q; the exact determination of the breakpoints is not possible at present due to the similar banding characteristics of the two segments involved in the translocation.

Incomplete trisomy 22. I. Familial 11/22 translocation with 3:1 meiotic disjunction. Delineation of a common clinical picture and report of nine new cases from six families.

The total dose of medical x irradiation ever received by 465 parents of children with Down's syndrome was compared with the corresponding dose for 465 parents of children with other severe congenital handicaps, matched for time of birth and maternal age. The mothers of those with Down's syndrome had had more total x rays, both in number and dose, before the conception, although overall the difference did not reach a significant level. However, mothers of the cases had received significantly more x rays ten years or more before the conception of the cases. No significant difference was found between the histories of the fathers of the cases and the controls. The practical and theoretical implications of the findings are discussed. (auth)

M Ray

Papers

Familial occurrence of trisomy 22.